In the past decade, protein folding has gained wider recognition and acceptance as an important field of[unreadable] biomedical research due, in part, to the growing number of examples of protein misfolding that have been[unreadable] linked to human diseases. In most cases, the misfolding event results in the formation of intermolecular[unreadable] aggregates and higher-ordered structures, often leading to the characteristic plaques known as amyloid. One[unreadable] aim of this research is to monitor the changes in protein conformation that precede aggregation in a unique[unreadable] environment where intermolecular interactions are prohibited. This will be achieved by encapsulating[unreadable] aggregation-prone polypeptides in the pores of a silica glass matrix by the sol-gel technique. Once[unreadable] encapsulated, solvent conditions will be altered to mimic those conditions that favor aggregation in solution.[unreadable] Circular dichroism spectroscopy will be used to detect intermediate states that differ in conformation from[unreadable] both the native and aggregated states of each protein and to screen for drug candidates or solutes that[unreadable] destabilize the intermediate conformation. Lysozyme, alpha-synuclein, a peptide fragment from the yeast[unreadable] prion Sup35, and a disease-associated variant of CuZn-superoxide dismutase will be among the first[unreadable] polypeptides studied by this approach.[unreadable] A second major aim of this research is to determine whether unfavorable backbone hydration serves as[unreadable] a dominant force in aggregation of misfolded proteins. This goal involves the testing of a new thermodynamic[unreadable] framework, developed by this laboratory, that accounts for the participation of bulk water in aqueous[unreadable] equilibria. A combination of density measurements and calorimetry techniques will be used to calculate the[unreadable] free energy of the bulk aqueous phase in the presence of specific solutes. Calorimetry studies will be[unreadable] followed by solubility measurements of model amide-containing compounds to elucidate the magnitude of[unreadable] backbone solvation energetics in protein folding and aggregation.[unreadable] This project aims to further our understanding of factors that promote protein aggregation. This research[unreadable] could lead to new strategies for therapeutic intervention of diseases caused by misfolding of proteins,[unreadable] including Alzheimer's, Parkinson's, and Huntington's diseases.[unreadable]